During times of nutritional excess, mammals store excess energy in adipocytes (fat cells). During times of nutritional insufficiency, triglycerides stored in the adipocytes are degraded to fatty acids and released to provide required energy. Many humans, for example, are not subjected to extended periods of low caloric intake, and as such, experience the accumulation of adipose tissue, leading to obesity.
There are several health risks associated with obesity, including the development of insulin resistance, hypertension, atherosclerosis, dyslipidemia, coronary heart disease, stroke, gallbladder disease, osteoarthritis, liver cirrhosis, sleep apnea and respiratory problems, and some cancers (endometrial, breast, and colon). Since most of these disorders are chronic conditions, they are expected to lead to rising medical costs and to create serious problems for society. Furthermore, despite the fact that these consequences of obesity have become well known in developed countries, the prevalence of obesity is rising rather than falling.
Obesity and obesity-related disorders are often treated by encouraging patients to lose weight by reducing their food intake or by increasing their exercise level, thereby increasing their energy output. A sustained weight loss of 5% to 10% of body weight has been shown to improve the co-morbidities associated with obesity and can lead to improvement of obesity-related disorders.
Weight loss drugs used for the treatment of obesity include orlistat (Davidson, M. H. et al. (1999) JAMA 281:23542), dexfenfluramine (Guy Grand, B. et al. (1989) Lancet 2:1142-5), sibutramine (Bray, G. A. et al. (1999) Obes. Res. &:189-98) and phentermine (Douglas, A. et al. (1983) Int. J. Obes. 7:591-5). However, the side effects of these drugs and anti-obesity agents can limit their use. Dexfenfluramine was withdrawn from the market because of suspected heart valvulopathy; orlistat is limited by gastrointestinal side effects; and the use of sibutramine is limited by its cardiovascular side effects, which have led to reports of deaths and its withdrawal from the market in at least Italy.
Some of the presently known target molecules in anti-obesity research include leptin, PPAR-γ and neuropeptide Y. But, because of the huge variety of causes for obesity, it is desirable to focus on molecules having different action mechanisms as targets for future drug development.
What are needed, then, are new methods and compositions for treating and/or preventing obesity. This and other needs in the art are addressed in whole or in part by the presently disclosed subject matter.